The immune system is tightly controlled to avoid the occurrence of autoimmunity when responding to various pathogens. This enantiostasis, allowing at the same time destruction of infected or transformed cells and self-tolerance, is guarded by several feedback mechanisms. Unfortunately, some of the mechanisms preventing auto-immunity are hijacked by cancers to attain immune escape. This evasion of immune destruction is based on several mechanisms including depletion of essential nutrients as well as accumulation of immunosuppressive metabolites. Thus, metabolic changes within the tumor microenvironment help to evade antigenic specific immune responses. In this respect, aberrations of the metabolism of the essential amino acid L-tryptophan have been described in various cancers. Notably, controlling the level of tryptophan is an important part of the host defense against invading pathogens as microbes need high concentrations of available tryptophan for optimal growth.
The degradation of L-(and D-) tryptophan to N-formylkynurenine is catalyzed by the heme dioxygenases tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). TDO and IDO do not share sequence homology. Although by distinct mechanisms, both TDO and IDO catalyze the first and rate-limiting step of tryptophan oxidation yielding kynurenine. Moreover, as IDO is upregulated by inflammatory cytokines such as type I and II interferon's, it is thought to be an important counter-regulatory enzyme, which controls disproportionate immune responses.
The impact of tryptophan metabolism on immune responses is well established. T cells sense low levels of tryptophan via the serine/threonine-protein kinase GCN2, which is then triggering proliferative arrest. Moreover, the tryptophan degradation product kynurenine binds the aryl hydrocarbon receptor (AHR); activation of AHR signaling induces formation of regulatory T cells.
Little is known about the function of TDO in cancer. Under physiologic conditions TDO is almost exclusively expressed at high amounts in the liver and—in lower levels—in the brain. Recently, it was described that tumors of different origin express TDO, especially melanoma, bladder cancer, hepatocellular carcinoma and glioblastoma (Pilotte et al., 2012). In a series of 104 human tumor cell lines of various histological types, 20 tumors expressed only TDO, 17 only IDO and 16 both enzymes (Pilotte et al., 2012). Moreover, in a preclinical model, TDO expression by tumors prevented their rejection by immunized mice (Pilotte et al., 2012).